Patient Demographics
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Division of Neurosurgery, Dalhousie University, Halifax, Nova Scotia, Canada
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Division of Neurosurgery, Dalhousie University, Halifax, Nova Scotia, Canada
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Summary
ACTH-secreting pituitary adenomas causing Cushing’s disease (CD) typically present with weight gain, whereas weight loss and hypokalemia in endogenous Cushing’s patients are suggestive of ectopic ACTH production. We report a case of CD presenting with atypical features of marked weight loss and hypokalemia. A 75-year-old female was admitted to the hospital with a history of profound weight loss, associated with uncontrolled hypertension, hyperglycemia, severe proximal muscle weakness, and hypokalemia. Subsequent investigations, including 24-h urinary free cortisol, 48-h low-dose dexamethasone suppression test, MRI of the sella, and bilateral inferior petrosal sinus sampling, confirmed CD without any evidence of ectopic ACTH production. She became eucortisolemic with medical therapy of ketoconazole and cabergoline, subsequently regained her weight, and became normokalemic. This case illustrates that patients with CD may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.
Learning points
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Patients with CD do not always present with classical clinical features and may present with symptoms and biochemical findings that would otherwise suggest ectopic ACTH production.
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While most patients with CD typically lose weight after biochemical remission, some patients gain weight after the normalization of cortisol levels.
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This case highlights the need to entertain a broad differential in patients presenting with hypokalemia and weight loss and the need to exclude hypercortisolemia.
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Summary
Non-islet cell tumour hypoglycemia (NICTH), typically mediated by insulin-like growth factor 2 (IGF-2), is a rare but highly morbid paraneoplastic syndrome associated with tumours of mesenchymal or epithelial origin. Outside of dextrose administration and dietary modification which provide transient relief of hypoglycemia, resection of the underlying tumour is the only known cure for NICTH. Available medical therapies to manage hypoglycemia include glucocorticoids, recombinant growth hormone, and pasireotide. We report two cases of IGF-2 mediated hypoglycemia. The first was managed surgically to good effect, highlighting the importance of a timely diagnosis to maximise the likelihood of a surgical cure. The second patient had unresectable disease and was managed medically, adding to a growing number of cases supporting the efficacy of glucocorticoids and recombinant growth hormone in NICTH.
Learning points
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Recurrent fasting hypoglycemia in the setting of a malignancy should raise suspicion of non-islet cell tumour hypoglycemia (NICTH), which is typically mediated by IGF-2.
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The initial workup for NICTH should include a serum glucose, C-peptide, insulin, insulin antibodies, beta-hydroxybutyrate, IGF-2, IGF-1, and sulphonylurea screen during a spontaneous or induced hypoglycemic episode.
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An IGF-2/IGF-1 ratio above 10 is highly suggestive of IGF-2-mediated hypoglycemia if the IGF-2 level is normal or elevated. False positives may be seen with sepsis and cachexia as both IGF-2 and IGF-1 are subnormal in these cases. A low IGF binding protein 3 (IGFBP3), such as in renal failure, may also result in a falsely normal or low IGF-2/IGF-1 ratio.
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Surgical resection of the associated tumour is curative in most NICTH cases.
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When the tumour is unresectable, moderate-dose glucocorticoids, low-dose glucocorticoids in combination with recombinant growth hormone, and pasireotide are medical therapies with promising results in controlling NICTH.
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Banting and Best Diabetes Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada
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Summary
Central diabetes insipidus (CDI) is a rare manifestation of acute myeloid leukemia (AML) with unclear etiology. When present, CDI in AML has most often been described in patients with chromosome 3 or 7 aberrations and no abnormalities on brain imaging. In this case, we present a woman with newly diagnosed AML t(12;14)(p12;q13) found to have diabetes insipidus (DI) with partial anterior pituitary dysfunction and abnormal brain imaging. While in hospital, the patient developed an elevated serum sodium of 151 mmol/L with a serum osmolality of 323 mmol/kg and urine osmolality of 154 mmol/kg. On history, she reported polyuria and polydipsia for 5 months preceding hospitalization. Based on her clinical symptoms and biochemistry, she was diagnosed with DI and treated using intravenous desmopressin with good effect; sodium improved to 144 mmol/L with a serum osmolality of 302 mmol/kg and urine osmolality of 501 mmol/kg. An MRI of the brain done for the assessment of neurologic involvement revealed symmetric high-T2 signal within the hypothalamus extending into the mamillary bodies bilaterally, a partially empty sella, and loss of the pituitary bright spot. A pituitary panel was completed which suggested partial anterior pituitary dysfunction. The patient’s robust improvement with low-dose desmopressin therapy along with her imaging findings indicated a central rather than nephrogenic cause for her DI. Given the time course of her presentation with respect to her AML diagnosis, MRI findings, and investigations excluding other causes, her CDI and partial anterior pituitary dysfunction were suspected to be secondary to hypothalamic leukemic infiltration.
Learning points
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Leukemic infiltration of the pituitary gland is a rare cause of central diabetes insipidus (CDI) in patients with acute myeloid leukemia (AML).
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Patients with AML and CDI may compensate for polyuria and prevent hypernatremia with increased water intake.
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AML-associated CDI can require long-term desmopressin treatment, independent of AML response to treatment.
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Summary
An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC)/paraganglioma is the cause of ectopic Cushing’s syndrome (CS) in 5.2% of cases reported in the literature. We present a previously healthy 43-year-old woman admitted to our hospital with cushingoid features and hypertensive urgency (blood pressure = 200/120 mmHg). Her 24-h urinary free cortisol was >4270 nmol/day (reference range (RR) = 100–380 nmol/day) with a plasma ACTH of 91.5 pmol/L (RR: 2.0–11.5 pmol/L). Twenty-four-hour urinary metanephrines were increased by 30-fold. Whole-body CT demonstrated a 3.7-cm left adrenal mass with a normal-appearing right adrenal gland. Sellar MRI showed a 5-mm sellar lesion. MIBG scan revealed intense uptake only in the left adrenal mass. She was managed pre-operatively with ketoconazole and phenoxybenzamine and underwent an uneventful left laparoscopic adrenalectomy, which resulted in biochemical resolution of her hypercortisolemia and catecholamine excess. Histology demonstrated a PCC (Grading System for Adrenal Pheochromocytoma and Paraganglioma score 5) with positive ACTH staining by immunohistochemistry. A PCC gene panel showed no mutations and there has been no evidence of recurrence at 24 months. This case highlights the difficult nature of localizing the source of CS in the setting of a co-existing PCC and sellar mass.
Learning points
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An adrenocorticotropic hormone (ACTH)-producing pheochromocytoma (PCC) is an important item to be considered in all patients presenting with ectopic Cushing’s syndrome (CS).
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In exceptionally rare cases, patients with ectopic CS may present with multiple lesions, and a systematic approach considering all potential sources is crucial to avoid misdiagnosis.
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CS with a large adrenal mass but lacking contralateral adrenal atrophy should raise suspicion of an ACTH-dependent process.
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In patients with clinical suspicion of PCC, clinicians should be mindful of the use of steroids and beta-blockers without appropriate alpha blockade as they may precipitate an adrenergic crisis.
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Summary
Familial nonautoimmune hyperthyroidism (FNAH) is rare and occurs due to a constitutively activating thyroid-stimulating hormone receptor (TSHR) germline mutation. Forty-one families with FNAH have been reported so far. In the study, 17 of 41 families were not diagnosed with FNAH until three generations or more were described with hyperthyroidism. We report a case of FNAH diagnosed in the third generation. The index patient was diagnosed with hyperthyroidism at age 3. Large fluctuations in thyroid hormone levels occurred during anti-thyroid drug treatment, and he developed a goiter. The patient’s mother had similar history, requiring two surgical interventions and radioiodine treatment. The younger brother of the index patient did not experience large thyroid hormone level fluctuations, nor increased thyroid growth. A heterozygous TSHR c.1357A>G mutation, resulting in a M453V amino acid exchange, was detected in all three patients leading to FNAH diagnosis, with complete genotype–phenotype segregation. Based on Sorting intolerant from tolerant (SIFT) and PolyPhen2 scores of 0.01 and 0.99, respectively, an effect on protein function can be assumed. As illustrated by this family with FNAH, total thyr oidectomy is necessary for patients with nonautoimmune hyperthyroidism. Development of goiter is common, anti-thyroid drug treatment is often difficult, and remission of hyperthyroidism does not occur after discontinuation of anti-thyroid drug treatment. Thus, early diagnosis and appropriate treatment of FNAH is necessary to avoid predictable, unnecessary complications and further surgical interventions.
Learning points
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In the study, 19/42 cases of familial nonautoimmune hyperthyroidism (FNAH), including the reported case, were not diagnosed as FNAH until the third generation; this lead to suboptimal treatment and frequent relapses of nonautoimmune hyperthyroidism (NAH).
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Detection of thyroid-stimulating hormone receptor (TSHR) mutations in patients with suspected FNAH to confirm diagnosis is essential to ensure proper treatment for the patient and further affected family members.
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NAH will persist without proper treatment by total thyroidectomy.
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Symptoms and age of onset may vary between family members
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All family members with a TSHR germline mutation should be monitored with thyroid-stimulating hormone and for symptoms throughout their lives.
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Summary
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare, autosomal recessive disorder caused by mutations in the SLC34A3 gene that encodes the renal sodium-dependent phosphate cotransporter 2c (NaPi-IIc). It may present as intermittent mild hypercalcemia which may attract initial diagnostic attention but appreciation of concomitant hypophosphatemia is critical for consideration of the necessary diagnostic approach. A 21-year-old woman was assessed by adult endocrinology for low bone mass. She initially presented age two with short stature, nephrocalcinosis and mild intermittent hypercalcemia with hypercalciuria. She had no evidence of medullary sponge kidney or Fanconi syndrome and no bone deformities, pain or fractures. She had recurrent episodes of nephrolithiasis. In childhood, she was treated with hydrochlorothiazide to reduce urinary calcium. Upon review of prior investigations, she had persistent hypophosphatemia with phosphaturia, low PTH and a high-normal calcitriol. A diagnosis of HHRH was suspected and genetic testing confirmed a homozygous c.1483G>A (p.G495R) missense mutation of the SLC34A3 gene. She was started on oral phosphate replacement which normalized her serum phosphate, serum calcium and urine calcium levels over the subsequent 5 years. HHRH is an autosomal recessive condition that causes decreased renal reabsorption of phosphate, leading to hyperphosphaturia, hypophosphatemia and PTH-independent hypercalcemia due to the physiologic increase in calcitriol which also promotes hypercalciuria. Classically, patients present in childhood with bone pain, vitamin D-independent rickets and growth delay. This case of a SLC34A3 mutation illustrates the importance of investigating chronic hypophosphatemia even in the presence of other more common electrolyte abnormalities.
Learning points:
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Hypophosphatemia is an important diagnostic clue that should not be ignored, even in the face of more common electrolyte disorders.
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HHRH is a cause of PTH-independent hypophosphatemia that may also show hypercalcemia.
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HHRH is a cause of hypophosphatemic nephrocalcinosis that should not be treated with calcitriol, unlike other congenital phosphate wasting syndromes.
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Some congenital phosphate wasting disorders may not present until adolescence or early adulthood.
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Summary
We report a case of metastatic papillary thyroid carcinoma presenting with a recurrent right-sided cervical lymph node necrotic cyst. A 55-year-old woman presented with a 3-month history of a right-sided upper neck mass following an upper respiratory tract infection. Past medical history includes a right-sided nephrectomy secondary to a benign renal tumor and hypertension. She was evaluated by Otolaryngology, and fine-needle aspiration was performed. The mass recurred 2 months following aspiration. Ultrasound of the neck showed a 2.2 × 1.4 × 1.9 cm right cervical lymph node with a small fatty hilum but a thickened cortex. Neck computed tomography (CT) scan showed a well-defined 2.3 cm mass in the right upper neck corresponding to a necrotic cervical lymph node at level IIA. It also revealed a 7 mm calcified left thyroid nodule. Cytology revealed a moderate collection of murky fluid with mildly atypical cells presumed to be reactive given the clinical history of infection. The cyst had re-grown 2 months following aspiration. Excisional biopsy was performed and revealed metastatic classic papillary thyroid carcinoma (PTC). Subsequently, a total thyroidectomy and right neck dissection was performed. Pathology confirmed metastatic unifocal classic PTC of the right thyroid lobe and two lymph node metastases out of a total of 17 resected lymph nodes. The patient underwent radioactive iodine ablation. Subsequent I-131 radioiodine whole-body scan showed no evidence of metastases. In conclusion, metastatic PTC should be considered in the differential diagnosis of a recurrent solitary cystic cervical lymph node.
Learning points:
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Metastatic PTC should be considered in the differential diagnosis of a recurrent solitary cystic cervical lymph node.
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A dedicated thyroid ultrasound is the preferred modality for identifying thyroid lesion over computed tomography.
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There is a risk of non-diagnostic cytology following FNA for cystic neck lesions, largely predicted by the cyst content of the nodule.
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Summary
Multifocal papillary thyroid carcinoma (PTC) is common and the number of tumor foci rarely exceeds ten. The mechanism of multifocal disease is debated, with the two main hypotheses consisting of either intrathyroidal metastatic spread from a single tumor or independent multicentric tumorigenesis from distinct progenitor cells. We report the case of a 46-year-old woman who underwent total thyroidectomy and left central neck lymph node dissection after fine-needle aspiration of bilateral thyroid nodules that yielded cytological findings consistent with PTC. Final pathology of the surgical specimen showed an isthmic dominant 1.5 cm classical PTC and over 30 foci of microcarcinoma, which displayed decreasing density with increasing distance from the central lesion. Furthermore, all malignant tumors and lymph nodes harbored the activating BRAF V600E mutation. The present case highlights various pathological features that support a mechanism of intraglandular spread, namely a strategic isthmic location of the primary tumor, radial pattern of distribution and extensive number of small malignant foci and BRAF mutational homogeneity.
Learning points:
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Multifocal papillary thyroid carcinoma (PTC) is commonly seen in clinical practice, but the number of malignant foci is usually limited to ten or less.
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There is no clear consensus in the literature as to whether multifocal PTC arises from a single or multiple distinct tumor progenitor cells.
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Strategic location of the dominant tumor in the thyroid isthmus may favor intraglandular dissemination of malignant cells by means of the extensive lymphatic network.
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An important pathological finding that may be suggestive of intrathyroidal metastatic spread is a central pattern of distribution with a reduction in the density of satellite lesions with increasing distance from the dominant focus.
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PTCs originating from the isthmus with intraglandular metastatic dissemination behave more aggressively. As such, a more aggressive treatment course may be warranted, particularly with regard to the extent of surgery.
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Summary
A 29-year-old G4A3 woman presented at 25 weeks of pregnancy with progressive signs of Cushing’s syndrome (CS), gestational diabetes requiring insulin and hypertension. A 3.4 × 3.3 cm right adrenal adenoma was identified during abdominal ultrasound imaging for nephrolithiasis. Investigation revealed elevated levels of plasma cortisol, 24 h urinary free cortisol (UFC) and late-night salivary cortisol (LNSC). Serum ACTH levels were not fully suppressed (4 and 5 pmol/L (N: 2–11)). One month post-partum, CS regressed, 24-h UFC had normalised while ACTH levels were now less than 2 pmol/L; however, dexamethasone failed to suppress cortisol levels. Tests performed in vivo 6 weeks post-partum to identify aberrant hormone receptors showed no cortisol stimulation by various tests (including 300 IU hLH i.v.) except after administration of 250 µg i.v. Cosyntropin 1–24. Right adrenalectomy demonstrated an adrenocortical adenoma and atrophy of adjacent cortex. Quantitative RT-PCR analysis of the adenoma revealed the presence of ACTH (MC2) receptor mRNA, while LHCG receptor mRNA was almost undetectable. This case reveals that CS exacerbation in the context of pregnancy can result from the placental-derived ACTH stimulation of MC2 receptors on the adrenocortical adenoma. Possible contribution of other placental-derived factors such as oestrogens, CRH or CRH-like peptides cannot be ruled out.
Learning points:
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Diagnosis of Cushing’s syndrome during pregnancy is complicated by several physiological alterations in hypothalamic–pituitary–adrenal axis regulation occurring in normal pregnancy.
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Cushing’s syndrome (CS) exacerbation during pregnancy can be associated with aberrant expression of LHCG receptor on primary adrenocortical tumour or hyperplasia in some cases, but not in this patient.
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Placental-derived ACTH, which is not subject to glucocorticoid negative feedback, stimulated cortisol secretion from this adrenal adenoma causing transient CS exacerbation during pregnancy.
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Following delivery and tumour removal, suppression of HPA axis can require several months to recover and requires glucocorticoid replacement therapy.
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Summary
Congenital hypothyroidism requires prompt treatment to prevent adverse health outcomes. Poor intestinal levothyroxine absorption can complicate management. We present a case of a term female newborn with necrotizing enterocolitis (NEC) requiring subtotal ileum resection. Congenital hypothyroidism was diagnosed by newborn screening. Treatment was complicated by intestinal malabsorption of levothyroxine. Intravenous levothyroxine substitution restored euthyroidism and supraphysiologic PO doses subsequently maintained a euthyroid state. After several months, the required levothyroxine dose was weaned down to typical recommended dosing. In conclusion, small bowel resection secondary to NEC may lead to malabsorption of oral levothyroxine. An intravenous levothyroxine dose of approximately 50% typical PO dosing is effective in providing rapid normalization of free T4 and TSH. High PO doses may be required to maintain euthyroidism. Close thyroid function monitoring and immediate therapy adjustment are essential as the individual absorption may vary widely. Normal absorption levels may be regained due to adaption of the neonatal intestines.
Learning points:
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In neonates with malabsorption after ileum resection intravenous levothyroxine replacement should be used to provide normalization of free T4 and TSH.
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Very high doses of up to 500% usual oral levothyroxine may be required to maintain euthyroidism. The estimated degree of malabsorption can be used to determine the initial dose.
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Close thyroid function monitoring and immediate therapy adjustment are essential as the absorption and intestinal adaption may vary widely.
